Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDJRZ0P)

• DOT Name: Organic solute transporter subunit alpha (SLC51A)
• Synonyms: OST-alpha; Solute carrier family 51 subunit alpha
• Gene Name: SLC51A
• Related Disease: Cholestasis, progressive familial intrahepatic, 6
• UniProt ID: OSTA_HUMAN
• Pfam ID: PF03619
• Sequence:
  MEPGRTQIKLDPRYTADLLEVLKTNYGIPSACFSQPPTAAQLLRALGPVELALTSILTLL
  ALGSIAIFLEDAVYLYKNTLCPIKRRTLLWKSSAPTVVSVLCCFGLWIPRSLVLVEMTIT
  SFYAVCFYLLMLVMVEGFGGKEAVLRTLRDTPMMVHTGPCCCCCPCCPRLLLTRKKLQLL
  MLGPFQYAFLKITLTLVGLFLVPDGIYDPADISEGSTALWINTFLGVSTLLALWTLGIIS
  RQARLHLGEQNMGAKFALFQVLLILTALQPSIFSVLANGGQIACSPPYSSKTRSQVMNCH
  LLILETFLMTVLTRMYYRRKDHKVGYETFSSPDLDLNLKA
• Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood. Efficiently transports the major species of bile acids (taurocholate). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids. Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols. Able to transport eicosanoids such as prostaglandin E2.
• Tissue Specificity: Widely expressed with a high expression in ileum. Expressed in testis, colon, liver, small intestine, kidney, ovary and adrenal gland; and at low levels in heart, lung, brain, pituitary, thyroid gland, uterus, prostate, mammary gland and fat.
• KEGG Pathway: Bile secretion (hsa04976)
• Reactome Pathway: Recycling of bile acids and salts (R-HSA-159418)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholestasis, progressive familial intrahepatic, 6	DISY0XDY	Limited	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Organic solute transporter subunit alpha (SLC51A) increases the response to substance of Cisplatin.	[26]

29 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Organic solute transporter subunit alpha (SLC51A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Organic solute transporter subunit alpha (SLC51A).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Organic solute transporter subunit alpha (SLC51A).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Organic solute transporter subunit alpha (SLC51A).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Organic solute transporter subunit alpha (SLC51A).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Organic solute transporter subunit alpha (SLC51A).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Organic solute transporter subunit alpha (SLC51A).	[16]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid increases the expression of Organic solute transporter subunit alpha (SLC51A).	[17]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[18]
Chenodiol	DMQ8JIK	Approved	Chenodiol increases the expression of Organic solute transporter subunit alpha (SLC51A).	[19]
Bosentan	DMIOGBU	Approved	Bosentan increases the expression of Organic solute transporter subunit alpha (SLC51A).	[20]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the expression of Organic solute transporter subunit alpha (SLC51A).	[17]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[21]
Budesonide	DMJIBAW	Approved	Budesonide increases the expression of Organic solute transporter subunit alpha (SLC51A).	[13]
Cholic acid	DM7OKQV	Approved	Cholic acid increases the expression of Organic solute transporter subunit alpha (SLC51A).	[17]
Amoxicillin	DMUYNEI	Approved	Amoxicillin increases the expression of Organic solute transporter subunit alpha (SLC51A).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Organic solute transporter subunit alpha (SLC51A).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[21]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Organic solute transporter subunit alpha (SLC51A).	[7]
	DM9CEI5		increases the expression of Organic solute transporter subunit alpha (SLC51A).	[13]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Organic solute transporter subunit alpha (SLC51A).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Organic solute transporter subunit alpha (SLC51A).	[25]

References

• [1] Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea. Hepatology. 2020 May;71(5):1879-1882. doi: 10.1002/hep.31087.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [13] Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos. 2009 Jul;30(5):241-58.
• [14] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [17] Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures. Toxicol Sci. 2014 Oct;141(2):538-46. doi: 10.1093/toxsci/kfu151. Epub 2014 Jul 23.
• [18] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [19] Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1124-30. doi: 10.1152/ajpgi.00539.2005. Epub 2006 Jan 19.
• [20] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [21] Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: Role of NRF2 and FXR pathways. Food Chem Toxicol. 2021 Dec;158:112664. doi: 10.1016/j.fct.2021.112664. Epub 2021 Nov 9.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans. PLoS One. 2011;6(7):e21920. doi: 10.1371/journal.pone.0021920. Epub 2011 Jul 6.